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Estrogen receptor stereochemistry: receptor binding and hormonal responses
K S Korach1, L A Levy, P J Sarver
1Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Journal of Steroid Biochemistry
|January 1, 1987
Summary
Diethylstilbestrol (DES) analogs were used to investigate estrogen-induced uterine responses. Researchers found that specific estrogen receptor (ER) interactions, not just ER levels, dictate distinct genomic outcomes like protein and DNA synthesis.
Area of Science:
- Endocrinology
- Molecular Biology
- Genomics
Background:
- Estrogen stimulation of the uterus triggers complex biochemical events, including protein synthesis, DNA synthesis, and mitosis.
- These estrogen-induced genomic responses are traditionally viewed as interconnected.
Purpose of the Study:
- To differentiate specific genomic responses previously thought to be interrelated.
- To investigate the role of stereochemistry in estrogen analog activity.
Main Methods:
- Utilized diethylstilbestrol (DES) and its analogs (indenestrol A, indenestrol B, indanestrol, pseudo DES) as molecular probes.
- Separated enantiomers of indenestrol A using chiral HPLC.
- Performed competitive binding assays and nuclear translocation experiments with mouse uterine estrogen receptors (ER).
- Assessed induction of glucose 6-phosphate dehydrogenase (G-6-PD), progesterone receptor (PR), ornithine decarboxylase (ODC), and DNA synthesis.
Main Results:
- Estrogen analogs showed specific binding and nuclear translocation of ER, with chiral preference observed for indenestrol A enantiomers.
- Indenestrol B mimicked DES in inducing G-6-PD, while other analogs had weak activity.
- All DES compounds stimulated PR induction, but only DES and indenestrol B significantly induced ODC and uterine DNA synthesis.
- Pseudo DES increased uterine cell height without increasing cell numbers, suggesting independent regulation.
Conclusions:
- Estrogen receptor (ER), progesterone receptor (PR), and G-6-PD induction are not coupled events.
- Specific uterine responses depend on the ligand-receptor complex structure and its interaction with genomic acceptor sites.
- Estrogen-induced uterine growth involves distinct, potentially separately regulated pathways.